Infection with the systemic fungi, Histoplasma capsulatum and Blastomyces dermatitidis afflict a large proportion of the population of the United States. H. capsulatum is the leading cause of fungal respiratory disease within the U.S. Both organisms are prevalent in the southeastern and Midwestern U.S., and they continue to take a toll on the health of the population at risk. It is unlikely that either of these will be controlled through public health measures since they are environmental fungi whose niches are difficult to detect. This proposal entitled "Defending Against Systemic Mycoses" represents a collaborative and synergistic effort among 4 laboratories in three institutions. The four principal investigators have a long-standing interest in the study of either or both of these fungi. Their combined research experience exceeds 70 years. Although located in different institutions, they have collaborated informally and formally on many occasions. Examples of the latter include co-authored manuscripts and shared NIH grants. The focus of this proposal will be to unearth the basic mechanisms of host response and fungal survival in order to create new and exciting means to prevent and/or treat these vexing microbial pathogens. Four projects are presented in this proposal. Dr. Deepe is the PI of the MRU and will be responsible for all the scientific performance of the grant. Project 1, led by Dr. Simon Newman, will determine the influence of cyclophilin as a ligand on H. capsulatum yeast for dendritic cells and to examine the role that this fungal molecule may play in modulating phagocyte biology including dendritic cells. Project 2 is headed by Dr. Bruce Klein, who will examine the novel observation that vaccination with a Bad1 mutant of B. dermatitidis or viable H. capsulatum can protect mice that lack CD4+ cells. This exciting finding suggests that immunosuppressed individuals, especially those who lack this cell population or in whom this cell population is dysfunctional, can be immunized against these pathogenic fungi. Project 3 headed by Dr. Deepe will examine the immunologic mechanisms that underpin reactivation histoplasmosis. This form of infection is thought to be one of the important means by which immunosuppressed as well as immunocompetent individuals develop progressive infection. Dr. Deepe has created a mouse model of reactivation disease and has demonstrated that B cells may exert a pivotal influence on the severity of reactivation. Project 4 is led by Dr. William Goldman, who has provided many new insights into the molecular biology of H. capsulatum. In this proposal he will examine the contribution of alpha (1,3) glucan to the virulence of H. capsulatum. His work will seek to understand the regulation of genes involved in synthesis of this moiety and the ability of this molecule to be a fungal drug target. The collaborative and synergistic effort manifested by this group of investigators will provide new and exciting information regarding prevention and/or treatment of these problematic fungi.